Figure 3 shows ICU survivors’ adjusted probabilities of ICU readmission and discharge to a destination other than home according to the percentage of total eligible ABCDEF bundle elements performed during the patient’s 7 days in the ICU (or until hospital discharge, if before 7 days). With more ABCDEF bundle elements performed, the risk of survivor readmission to an ICU or discharged to a facility significantly decreased (p < 0.002 and p < 0.0001, respectively).
The full results of our tipping point analysis are presented in SDC Table 2 (Supplemental Digital Content 1, http://links.lww.com/CCM/E101). An example of what the analysis showed is provided by looking at the outcome of mechanical ventilation. An odds ratio (OR) of 0.08 between a one-unit change in severity of illness and mechanical ventilation would be needed to tip our observed results to inconclusivity (closer to 1, or a null result)–an extremely large and unrealistic effect size. Using a more conservative approach (SDC Methods 2, Supplemental Digital Content 1, http://links.lww.com/CCM/E101), we would still need an unlikely strong OR of 0.13 to move our original results to inconclusivity (closer to 1).
The results of the sensitivity analysis adjusting for severity of illness among the 950 patients with APACHE III scores available are reported in SDC Table 3 (Supplemental Digital Content 1, http://links.lww.com/CCM/E101). This sensitivity analysis demonstrated statistically significant relationships between ABCDEF Bundle performance and the odds of remaining on mechanical ventilation, in delirium, or receiving restraints. The findings along with ICU discharge and significant pain were qualitatively similar to the original analyses reported above for the entire cohort. No statistically significant associations were seen in the sensitivity analysis between ABCDEF bundle use and hospital discharge or discharge disposition. The absence of a statistically significant difference in the latter outcomes in this small subgroup analysis could be due to lack of power in the reduced subset or a true confounding effect from severity of illness.
The goal of this study was to evaluate the relationship between ABCDEF bundle performance and patient-centered outcomes from a diverse set of ICUs that participated in the ICU Liberation Collaborative. We sought to determine whether the bundle benefits reported in other, smaller cohorts (17 , 18) would be reproducible in this larger and more diverse cohort that included multiple ICU types (medical, surgical, neurological, trauma) and academic, community, and federal hospitals throughout the United States and Puerto Rico. These data from over 15,000 patients in 68 ICUs showed a consistent signal of improved outcomes regardless of whether bundle performance was complete or proportional (i.e., across a “dose” range). Patients who received more of the ABCDEF bundle elements each day had a large and significantly improved likelihood of surviving; having less coma, delirium, and physical restraint; being liberated from ventilation; avoiding ICU readmission; and being discharged home.
Considering the burden that PICS imposes on ICU survivors, their family members, and society as a whole (5 , 7 , 42–45), there is a driving unmet need to improve both ICU structure and culture for the more than five million patients admitted to ICUs in the United States each year (46–51). One obvious tactic is to bundle proven interventions together. While some bundles and toolkits have been successful in improving patient outcomes (19–21), others have not (22). When assorted interventions that had proven effective individually (i.e., low tidal volume ventilation, moderate sedation, central venous and urinary catheter use, head of bed elevation, thromboembolism prophylaxis, and nutrition) were bundled together and implemented in 118 ICUs in Brazil, patient outcomes did not change (22). By contrast, the philosophy behind building the ABCDEF bundle was that the features had to be interdependent and clinically synergistic.
Despite early signals that the bundle would be advantageous, we know that clinical reproducibility in medical research is often poor (52 , 53). When translating animal models to human studies, the most consistent predictor of reproducibility is the dose-response effect of an intervention (54). Guyatt et al (55) emphasized that finding a dose-response gradient in clinical investigations upgrades the quality of evidence. Our investigation showed clear dose-response relationships between daily ABCDEF bundle performance and outcomes (Figs. 1–3) considered important to ICU patients, families, and the clinicians caring for them. Similar dose-response relationships were found in a 6,000-patient cohort study that showed that every 10% increase in ABCDEF bundle compliance independently predicted a 15% improvement in both survival and days without coma and delirium (18).
In our cohort, the likelihood of a patient experiencing significant episodes of pain varied with bundle performance (Fig. 2). Interestingly, the complete bundle performance analysis did not show this relationship, which could be a type II error. However, a more likely explanation is that, once sites had implemented bundle element A and started systematically assessing patients for pain using appropriate tools, significant pain that would otherwise have gone undetected was identified more frequently (i.e., a reporting bias as performance of bundle element A increased). It is also plausible that patients who received different elements of the bundle (i.e., proportions of the bundle rather than all or none) were at risk for significant pain. For example, if a patient was not receiving adequate pain assessments but was receiving early mobilization, staff members may not have recognized and managed pain appropriately. Finally, it could also be possible that patients with significant pain (which includes moderate and severe pain) might be more likely to have more of the bundle elements completed. Future research is needed in this area to better understand this relationship.
There are six main study limitations. First, this was not a randomized study design nor did we have access to concurrent controls. Therefore, unmeasured covariates may influence the observed associations between ABCDEF bundle performance and outcomes. For example, the bundle components introduce many elements of human connectedness (waking patients, holding their hand and walking with them, and their regaining a sense of agency) that could influence the outcomes and cannot be captured quantitatively. Future randomized controlled studies of this bundle intervention are being planned (56).
Second, the ICU Liberation Collaborative intentionally included a variety of ICU types as part of a larger effort to understand the impact of the ABCDEF bundle on various types of critically ill patients, as well as to gain better understanding of implementation strategies that are unique to each setting. While this current report includes a minority of patients from neurologic, trauma, and cardiac settings, the results are consistent with those from the original ABCDE Bundle study (17), which included medical, surgical, trauma, neurologic, and cardiac patients. The consistency further supports the message that the ABCDEF bundle can apply to all critical care patients. However, future inquiry is still needed to explore the full impact of the ABCDEF bundle in these specific populations as well as particular implementation challenges.
Third, our patient-level outcomes are not wholly independent of one another (i.e., there is a relationship between analyses of hospital death and discharge), and are assessed within a very short time frame, during which many of our patients did not experience these outcomes (requiring them to be censored). Future work could consider a longer follow-up period alongside competing risks regression to account for patients who, for example, die before they are discharged.
Fourth, similarly to other collaboratives and QI projects and many studies, the ICU Liberation Collaborative did not have the funds to support data accuracy auditing. While all sites were provided with a detailed standard operating procedures manual, offered formal data collection training, and were provided with ongoing as needed support, it is possible that errors may have occurred during the data collection process, introducing the possibility of reporting bias.
Fifth, this cohort analysis is from patient data collected within the scope of a large QI project that collected a minimum and de-identified dataset, both of which limited our ability to answer certain questions. The site personnel in the ICU Liberation Collaborative were unpaid and time constraints mandated that we collect data on a limited number of consecutively admitted ICU patients at each participating institution for a limited period (up to 7 days). These data therefore may not apply to patients with longer ICU stays and especially those who develop chronic critical illness. Additionally, data abstraction for these bundle elements is cumbersome because individual elements of the ABCDEF bundle are often separate and disconnected in current designs of electronic health record (EHR) systems (e.g., EPIC and CERNER) which often have siloed screens and standard views that vary significantly depending on the user and institution. Userfriendly EHR platforms that are easily adaptable would better support ongoing QI and research in this area (26 , 34 , 56–58). Additionally, data collected by multiple team members should be seamlessly displayed on integrated EHR dashboards accessible by all team members so that patients’ ABCDEF bundle progress can be monitored in a collaborative way (e.g., one-stop dashboard screen access for all bundle elements).
Finally, this initiative did not collect uniform severity of illness data because of funding limitations. Only 6% of patients had severity of illness scores from the same scoring system and those patients were all from six sites that already tracked the scores. This precluded directly adjusting for this covariate, which would help understand the very large effect sizes we have found previously from this bundle (18). Our sample size (over 15,000 ICU patients and nearly 50,000 patient-days of data) and the inclusion of 18 covariates chosen a priori, adjusting as possible for patient characteristics and measures of baseline health and acuity, are robust but do not completely remove the potential benefit of adjusting for severity of illness.
However, because of the importance of this limitation, we conducted two additional sensitivity analyses. First, we conducted a “tipping point” analysis (37 , 38), which is described and presented in SDC Table 2 (Supplemental Digital Content 1, http://links.lww.com/CCM/E101). That type of analysis allowed us to quantify the amount of total unmeasured confounding needed to render our analysis inconclusive. The sensitivity analysis indicated that even if the true adjusted associations between ABCDEF bundle performance and all five in-ICU outcomes were smaller than observed after adjusting for severity of illness, they were still likely to be clinically relevant.
Additionally, in a very small (6%) subgroup of patients who had available APACHE III scores reported, we conducted a sensitivity analysis that directly incorporated severity of illness as an additional covariate into the original modeling (SDC Table 3, Supplemental Digital Content 1, http://links.lww.com/CCM/E101). While obviously limited in size and power, the analysis found similar changes in endpoints of ICU discharge, mechanical ventilation, delirium, significant pain, physical restraints, and discharge destination, all of which were consistent with the results of the main analysis. The likelihood of hospital discharge, although not significant, showed an inverse relationship with bundle compliance. With that exception, these two sensitivity analyses were generally consistent with and thus support the validity of the main findings of this report.
This cohort analysis from the ICU Liberation Collaborative demonstrates that the performance of the ABCDEF bundle results in significant and dose-related improvements in outcomes, including better survival, duration of mechanical ventilation, brain organ dysfunction (i.e., delirium and coma), physical restraint use, ICU readmission rates, and discharge disposition of ICU survivors. Additional unmeasured benefits often expressed during the collaborative represent excellent points for future work, such as the effect that full integration of the ABCDEF bundle has on making ICU care more collaborative, holistic, and patient centered, with an eye toward returning patients to their previous lives.
The following sites and members at each site participated in the ICU Liberation Collaborative and generated the data upon which this report is based: Advocate Christ Medical Center: Charles Alex, Nadia Abdessalam, George Gavrilos, Jill Sweeney; Atrium Health: Jaspal Singh, Julia Retelski, Lauren Macko, Brianne Riegel, Jennifer Cline; Aultman Hospital: Nihad Boutros, Amy Hiner, Jonas Sykes, Kim Dougan; Avera McKennan Hospital: Kari Taggart, Carol Leiferman, Fady Jamous, Kristy Colford; Banner University Medical Center Tucson: Alicia Johnson, Larry Deluca; Baptist Memorial Hospital Memphis: Jeffery Wright, Carole Schuh, Maria Zhorne; Berkley Medical Center (WV university): Phillip Aguila, Angela Girod, Chuck Steg, Donnie Kees, David Fillman; Cape Fear Valley Health System: Felicia McGarry, Samuel Wamathai Kimani, Kerstin Hudgins, Esteban Mery-Fernandez, Claudette Fragueiro, Lynn Bass; Cedars Sinai Medical Center: Bahar Mjos, Alice Chan, Robert Fellin, Michael Nurok, Todd Griner; Cleveland Clinic: Faith Factora, Kathleen Hill, Karoline Lubbeck, Roxanne Eaton, Dianne Havanchak; Columbia St. Mary’s: Antonio Salud II, Anne Putzer, Sara Harwood, Andi Gust, Cindy Keller; Community Regional Medical Center: Kim Pope, Krista Kaups, Jose Rendon, Catrina Cullen, Alice Evans, Melissa Reger, Paul Smith; Corona Regional Medical Center: Aimee French, Fernando Fierro, Kaveh Rezvan, Joon Kim; Edward Elmhurst Hospital: Mara Chiocca, Kim Clohecy, Keith Nguyen, Amy Rowe, Mohammed Sajed; Emory University Hospital: Jonathan Sevransky, Carolyn Holder, Stacey Campbell; Franciscan Health-Indianapolis: Imad Shawa, Kimberly Durham, LeeAnn McGinley-Wright, Cheryl Wolverton, Frank Lucas, Karen Hunt; Hannibal Hospital: Pranav Parikh, Kim Runquist, Pam Guilfoyle, Patti Gilbert; Harrison Medical Center: Griffith Blackmon, Patricia Hetrick, Cheryl Christian, Rima Kim, Len Schulmeister; HIMA San Pablo Caguas Hospital: Dra.Gloria Rodríguez Vega, Dr. Hector L Peniston Feliciano, Arlene Rivera, Eniliz E. Gerena, Jahaira Rentas, Ana M. Rodriguez, Wilma González, José R. Rodríguez; University of Puerto Rico, Medical Sciences Campus-SON: Milagros Figueroa-Ramos, C. Mabel Arroyo-Novoa; Houston Methodist Hospital: Christopher Cortes, Teal Riley, Rajashree Mondkar; Indiana University Health Arnett Hospital: Jennifer Hittle, Muhammad Ali, Katherine Douglass, Erin Hoag; Iowa Methodist Medical Center Unity Point: Sheryl Sahr, Sarah Pandullo, Lisa Kingery; Keck Hospital of USC: Perren Cobb, Kathrine Winnie, Geoff Cariker; Kettering Medical Center: Doug Paul, Delaine Adrian, Carol Severance, Melody Campbell; LAC+USC Medical Center: Santhi Kumar, Eileen Friesen-Mosher, Stephanie Summerville; Lake Cumberland Hospital: Sandra Schuldheisz, Courtney Troxell, Katrina Mounce; Lake Regional General Hospital: Kamen Rangelov, Stephanie Wheeler, Michael Smith; Northwestern Memorial Hospital: Jacqueline Kruser, Bryan Lizza, Megan Oakford, Leigh Anne Wild, Chris French; Novant Health Forsyth Medical Center: Christina Cassidy, Sandy Hunter, Barry Sigal, Sharon Cox, Lawson Millner; Novant Health PMC Presbyterian Medical Center: Wheeler Jervis, Deborah Briese, Laura Frantz; Oklahoma University Medical Center: Regina Ketts, Kammie Monarch, Pamela R. Roberts, Ruben Villanueva, Kris Wallace; Orange Regional Medical Center; Pali Momi Medical Center: Emilio Ganitano, Lorna Coloma, Jackie Scotka; Parkland Health & Hospital System: Brian Williams, Natalie Provenzale, Stacey Barker, Katherine Mapula; Parkview Community Hospital: Ahmed El Bershawi, Marlena DeMicco, Leonard Carreathers; Providence Portland Medical Center: David Hotchkin, Bev Lorhman, Julie Martinez; Providence St. Patrick Hospital: Will Surber, Nicole Marks, Marian Maxwell; Riverside University Health Systems: Arriti (Nikki) Mitial, Gigi McNicholl, Allison Flores, Walter Klein, Leah Patterson; Ronald Reagan UCLA Medical Center: Joseph Meltzer, Katrine Murray, Sheila Shirzi; WVU Medicine – Critical Care and Trauma Institute: Greg Schaefer, Shanna Watson, Karen Petros; Rush University Medical Center: Nicholas Panos, Sayona John, Valerie Musolf, Ankeet Patel, Payal Gurnani, Lillian Hall, Elizabeth Day, Barbara Gulczynski, Mark Yoder, Brenda Koverman, Diane Genaze, Michele Simler, Ruth Kleinpell, David Gurka, Gourang Patel, Brandon Bell, Maria Goetz, Amy Blackwood, Joseph Ceisel, Timothy Carrigan; Sarasota Memorial: Kirk Voelker, Karen Reynolds, Anit Legare, Melinda Bacallao; Scripps Mercy Hospital Chula Vista: John Perri, Deena Drake, Valeska Cid Donat, Terry Taylor, Alessio Bloesch; Sharp Grossmont Hospital: Barzan Mohedin, Ani Harter, Kareem Dally, Jill Limberg; South County Hospital: Bobbie Fay, Bashar Bash, Ellen Fales, Lisa Chatowsky, Siobhan Ryan; Spectrum Health Butterworth Hospital: Greg Marco, Nancy Bekken, Nick Ames, Stephen Fitch; St. Luke’s Hospital: Paula Brown, Hope Cranston Damato, Thomas Simon, Heather Thompson, Bhavna Desai; Sutter Health Memorial Medical Center: Roger Elias, Terry Lynch, Abigail Kurtz, Monika Rebalska, Pete Tomaino, Vio Burciu; Tennessee Valley Health System VA: Kelly Drumright, Margaret Russell, Shawn Sells, Julie Bastarache, John Barwise; The Ohio State Wexner Medical Center: Michele L. Weber, Kari Cape, Matthew Exline, Cindy Byrd, Connie McCarthy; Thomas Jefferson University Hospital: Michael Baram, Julie Rogan, Cara McDaniel, Miranda Tan; University of California San Francisco: Matthew Aldrich, Heidi Engel, Joyce Chang, Denise Barchas, Kathleen Puntillo; University of Michigan Hospital & Health Center: Connie Rickelmann, Megan Klei, James Miller, Jessica Cusac, Sharon Dickinson, Nikki Werner, Adam Carter, Lena Napolitano, Pauline Park; University of North Carolina Chapel Hill: Lydia Chang, Mikey Jernigan, Allison Driver; University of Wisconsin Hospital: Hee Soo Jung, Anna Krupp, Jeff Fish; VA Palo Alto Healthcare System: Juli Barr, Andrea Saito, Mylinh Ho, Elayne Rodriguez, Laura Zimmerman; Virginia Mason Medical Center: Aneal Gadgil, Markie Baxter, Ernesto Lopez; Washington Hospital Healthcare System: Carmen Agcaoili, Kathy Weinberg, Bhav Kaur, Elvie Ballar, Alisa Curry; Wooster Community Hospital: Bruce W. Arthur, Joann Panno, Jennifer Peterson, Karen Steiner.
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